Nitrogen-containing derivatives of 2,5-dichloro-3-nitrobenzoic acid



United States Patent Ofice 3 415,838 NITROGEN-CONTAIN ING DERIVATIVES F 2,5- DICHLOR0-3-NITROBENZOIC ACID Nathan N. Crounse and Robert J. Schumacher, Cincinnati,

Ohio, assignors to Sterling Drug Inc., New York, N .Y., a corporation of Delaware N0 Drawing. Continuation-impart of application Ser. No. 244,864, Dec. 17, 1962. This application May 20, 1965, Ser. No. 457,500

Claims. (Cl. 260306.8)

This application is a continuation-in-part of our copending United States Patent application Ser. No. 244,864, filed Dec. 17, 1962, now US. Pat. 3,228,833, issued Jan.l1,1966.

This invention relates to chemotherapeutic compositions useful in animal husbandry and in particular relates to compositions and methods for the prevention and suppression of coccidiosis.

Coccidiosis, a disease of great economic importance because of its epidemic nature and its destructiveness to poultry, is caused by protozoan organisms known as coccidia, and in particular, by certain species of the genus Eimeria. Coccidia gain access to the host by way of ingested food, drinking water, or soil contaminated with oocysts which are found in fecal droppings of fowl harboring the parasites. The coccidia multiply in the gastrointestinal tract and erode the epithelial tissues of the cecum and intestines, causing hemorrhage, weakness, emaciation, and digestive disturbances. The fowl which survive severe infections are left in a state of debilitation which substantially reduces their market value.

Of the numerous remedies which have been suggested for the control of coccidiosis, many are too inefficient, prohibitatively expensive, or too toxic for prophylactic administration. Moreover, with the previously available remedies there may be encountered such metabolic difiiculties as poisoning of the hematopoietic system and a subsequent reduction in the number of red and white blood cells, adverse effect on fertility, color, taste, or odor of eggs produced by the birds, and unpalatability of the flesh of the birds. The need for new and improved means for controlling coccidial infections in poultry has therefore remained a serious problem in the poultry industry.

It is an object of this invention to provide novel compounds which are useful as anticoccidial agents when administered to poultry in prophylactic quantities. It is another object of this invention to provide novel feed compositions useful for the prevention and suppression of coccidiosis in poultry. It is still another object of this invention to provide a new and useful method for the control of coccidiosis in poultry.

In accordance with the present invention, we have discovered that coccidiosis in .poultry can be prevented and suppressed by administering to the birds, preferably in combination with poultry feed, a small quantity of a compound of the general Formula I,

Hal

Hal N 02 I wherein X is a member of the group consisting of CONH CONHR, CONRR', CONHNHCOR CONHNRR, CONHOH, and CN, wherein R and R can be the same or different and are selected from the group consisting of lower-alkyl, .lower-alkenyl, phenyl, benzyl, pyridyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, and furyl. The foregoing radicals can be unsubstituted or they can be substituted by from one to three substituents 3,415,838 Patented Dec. 10, 1968 inert toward other functional groupings in the molecule, and Hal is halogen. Hence we have found that the above compounds possess an unobvious utility as intermediates for the preparation of medicated poultry feed compositions.

When representing lower-alkyl, R is a straight or branched-chain saturated hydocarbon radical preferably of from one to six carbon atoms. Examples of loweralkyl radicals are methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

When representing lower-alkenyl, R is a straightor branched-chain hydrocarbon radical preferably of from two to six carbon atoms and having at least one double bond. Examples of lower-alkenyl radicals are vinyl, allyl, methallyl, 1-(3-pentenyl), 1-(2,4-hexadienyl) and the like.

The lower-alkyl and lower-alkenyl-radicals and the benzyl, phenyl, pyridyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, and furyl radicals represented. in Formula I by R can be substituted with from one to three substituents which are inert toward other functional groupings in the molecule. The substituents are preferably of low molecular weight, and where there is more than one, they can -be the same or different. Examples of suitable inert substituents are hydroxy, halo, carboxy, amino, lower-alkylamino, di-(lower-alkyDamino, nitro, lower-alkoxy, and loweralkylmercapto. Examples of substituted radicals represented by R thus are, aminoethyl, 'dimethylaminopropyl, 2,3-dihydroxypropyl, -methoxyhexyl, 4-nitrophenyl, 3,4- dichlorophenyl, 4'-nitro-2'-chlorobenzyl, S-nitrO-Z-furyl, S-brorno-Z-thiazolyl, 4-methoxy-2-pyridyl and the like.

In Formula I, Hal represents halogen, and hence is selected from the group consisting of fluorine, chlorine, bromine, and iodine. Preferred halogens for the purposes of this invention because of the ready availability of necessary starting materials, are chlorine and bromine.

The amide compounds of Formula I are prepared by reacting a primary or secondary amine with an acylating agent derived from 2,5-dihalo-3-nitrobenzoic acid. Effectivc acylating agents are 2,5-dihalo-3-nitrobenzoyl halides, for example 2,5-dichloro-3-nitrobenzoyl chloride, 2,5-dibromo-3-nitrobenzoyl bromide, and the like. The acylating agents can be prepared from their corresponding acids according to general and well-known methods. As an example, 2,5-dichloro-3-nitrobenzoyl chloride can be prepared from 2,5-dichloro-3-nitrobenzoic acid and thionyl chloride either alone or in the presence of an inert solvent. Where the intermediate acid is not readily available, it can be prepared by reacting a p-dihalo-benzene (e.g., p-dibromobenzene, p-dichlorobenzene, p-difiuorobenzene, or p-diiodobenzene) with phosgene under Friedel-Crafts reaction conditions, followed by hydrolysis to 2,5-dihalobenzoic acid and subsequent nitration with a nitrating agent, for example a mixture of nitric and sulfuric acids.

The reaction of primary and secondary amines with 2,5-dihalo-3-nitrobenzoyl halide is preferably conducted at low temperatures (that is, below room temperature) to lessen the incidence of side reactions. Where the amine is water-soluble and inexpensive, as for example with methylamine, ethylamine and ethanolamine, is is convenient to add the 2,5-dihalo-3-nitrobenzoyl halide to an excess of the amine in water and ice, whereupon the desired amide separates in nearly pure form from the aqueous solution. Alternatively, the reaction can be conducted under Schotten-Baumann reaction conditions, that is, in the presence of ice and aqueous sodium hydroxide.

The compounds of Formula I wherein X is the cyano group can be prepared by dehydrating the corresponding compound wherein X is CONH with standard dehydrating reagents, for example, phosphorus pentoxide, phosphorus oxychloride, or thionyl chloride.

As another alternative the compounds of Formula I can be prepared by nitrating the corresponding 2,5-dihalobenzamides and 2,5-dihalobenzonitri1es with a nitrating agent, for example, fuming nitric acid.

In another of its aspects, our invention provides novel compositions for the prevention and suppression of coccidiosis in poultry which comprises poultry feed having dispersed therein as an effective anticoccidial ingredient a compound of the Formula I.

In another of its aspects, our invention provides a method for preventing and suppressing coccidiosis in poultry which comprises administering to the poultry a compound of Formula I.

In still another of its aspects, our invention provides the novel and useful compounds of Formula H Hal Hal N O 2 wherein X is a member selected from the group consisting of CONHR, CONRR, CONHNHCOR, CONHNRR', CONHOH and CN and Hal is halogen and wherein R and R are substituents identical to R and R described in Formula I.

The administration of compounds represented by Formula I has been found to protect poultry from coccidial infections. The compounds are useful for the prophylactic treatment of poultry both prior to and concurrently with exposure of the poultry to infection. It is most practical to administer the medicament daily to the poultry flock at a dosage level which affords continuous protection against coccidiosis.

Although the optimum prophylactic daily dosage of the above-described compounds varies according to the age and weight of the poultry, we have found that satisfactory results are obtained in the management of coccidiosis when each bird receives the medicament at a level of about 0.005 to 0.2 percent by weight of the daily diet of the bird. When administered in feed, the concentration of the anticoccidial ingredient therein can be varied considerably, and it is only necessary to adjust the concentration so that an effective dose of the compound is ingested by the bird in consuming its daily ration of food. Thus, good results are obtained when each bird is fed a commercial poultry feed containing about 0.005 to 0.2 percent by weight (that is 0.1-4 pounds per ton) of a medicament selected from the group represented by Formula I.

Feed compositions containing a medicament of Formula I in any desired amount can be readily prepared by dispersing the compound in the feed as the sole or part ration of the poultry, as by mechanically mixing the compound in finely ground form with the feed or dispersing a solution of the compound in the food and either removing the solvent, or, if the solvent is innocuous, allowing it to remain in the feed. The feed composition can be prepared either for direct use by mixing 0.005 to 0.2 percent of the medicament by weight with the feed; or, if desired, a concentrated pre-mix feed can be obtained by using a considerably larger percentage of medicament, for example, to 40 percent by weight, which is suitable for subsequent blending with a larger amount of the same or a different kind of poultry feed to arrive at the desired concentration of medicament for feeding.

In preparing the medicated feeds of our invention, there can be used any suitable poultry feed, such as a commercial mash of the starting, growing, or laying type, which will satisfactorily supply the normal nutritional requirements of the birds. These feeds commonly contain ground grains and various other added ingredients such as vitamins, minerals, powdered milk, meat or protein substitute, and the like.

The following examples will further illustrate our invention, without the latter being limited thereto.

4 EXAMPLE 1 2,5-dichloro-3-nitro-N-methylbenzamide A solution containing 236 g. (1.0 mole) of 2,5-dichloro-3-nitrobenzoic acid and g. (1.47 mole) of thionyl chloride in one liter of toluene was slowly heated and then refluxed until evolution of hydrogen chloride and sulfur dioxide was complete. The unreacted thionyl chloride and about two-thirds of the solvent were then distilled from the reaction mixture containing 2,5 dichloro- 3-nitrobenzoyl chloride. The latter was cooled and poured into a well-stirred solution containing a large excess of methylarnine in ice and water. The temperature of the resulting mixture was maintained below 20 C. by the addition of ice. The aqueous layer was decanted, and the organic phase was washed repeatedly with water. The crude 2,5-dichloro-3nitro-N-methylbenzamide which precipitated from the toluene layer was collected and recrystallized from ethanol. Pure 2,5-dichloro-3nitro-N-methylbenzamide thus prepared melted at 169.8171.0 C. (corr.)

2,5-dichloro-3nitro-N-methylbenzamide was dispersed uniformly in a basic poultry feed, producing medicated feed compositions containing from 0.00625 to 0.1 percent each by weight of medicament. These compositions and unmodified basic poultry feed were fed as the sole ration to six lots of nine 4-week old chickens of a White Plymouth Rock Cross. Forty-eight hours after this diet was started, the birds were inoculated with a multiple species inoculum consisting of 80,000 sporulated oocysts each of the species E. tenella, E. maxima, E. necatrix, and E. brunetti, 600,000 of E. accrvulina, and 400,000 of E. lzagani. Fourteen days after inoculation, the birds were weighed and tallied for death due to coccidiosis. The results are reported in the following Table I:

TABLE I Medication Ave. wt. in Ave. wt. gained Lot No. (percent) by grams at 14 days after Mortalit-ies weight of inoculation inoculation (Coccidiosis) the diet (in grams) 1 None 382 60 5 0.05 366 203 0 0.025 367 254 0 0. 0125 353 214 0 0.00625 375 228 0 6 0.1 336 247 0 EXAMPLE 2 TABLE II Medication Ave. wt. in Ave. wt. gained Lot N05 (percent) by grams at 14 days after Mortalities weight of inoculation inoculation (Coecidiosis) the diet (in grams) None 608 91 4 0. 05 663 177 0 0. 025 646 137 l 0. 0125 640 271 2 *Ten straight run six-week old White Plymouth Rock Cross chickens perlot.

EXAMPLE 3 2,5-dichloro-3nitro-N-ethylbenzamide Following the procedure given in Example 1, 2,5-dichlorobenzoic acid was reacted with thionyl chloride and ethylamine. Recrystallized from ethanol, the resulting 2,5-dichloro-3-nitro-N-ethylbenzamide melted at 161.2- 163.6 C. (corr.).

The efficacy of 2,5dichloro-3-nitro-N-ethylbenzamide in preventing and suppressing development of coccidiosis was tested as in Example 1, and the results are given in the following Table III:

The following examples of my invention are prepared according to the procedure of Example 1 by substituting the appropriate amine for the methylamine therein:

Example 4, 2,5-dichloro 3 nitro-N-(Z-hydroxyethyl) benzamide, having a melting point of l45.4-146.2 C. (corn).

Example 5, 2,5-dichloro 3 nitro-N,N-dimethylbcnzamide, having a melting point of 146.-0147.7 C. (corr.).

Example 6, 2,5-dichloro-3,4-dinitrobenzanilide, having a melting point of 2l9.0-220.2 C. (corn).

Example 7, 2,5-dichloro 3 nitro-N-(2-thiazolyl) benzaunide, melting with decomposition at 277.0-278.2 C. (corr.).

Example 8, 2,5-dichloro-3-nitro-N-(3-dimethylaminopropyl)benzamide, having a melting point of 91.496.2 C. (corr.).

Example 9, 2,5,3,4'-tetrachloro-3-nitrobenzanilide, havinga melting point'of 195-l97 C.

Example 10, 2,5-dichloro-S-nitrobenzohydroxamic acid, having a melting point of 180-182 C.

Example 11, 2,5-dichloro 3 nitro-N-sec.-butylbenzamide, having a melting point of 130.6-132.8 C. (corr.).

Example 12, 2,5 dichloro-3-nitro-N-isobutylbenzamide, having a melting point of 151.8153.0 C. (c0r1'.).

Example 13, 2,5-dichloro 3 nitro-N-tert.-butylbenzamide, having a melting point of 163.6-1652" C. (corr.).

Example 14, 2,5-dichloro-3-nitro-N-(1,l,3,3-tetramethylbutyl):benzamide, having a melting point of 154.6- 155.8 C. (corr.).

Example 15, 2,5-dichloro-3-nitro-N-(n-propyl)benzamide, having a melting point of 137.2l38.2 C. (corn).

Example 16, 2,5-dichloro-3-nitro-N-(n butyDbenzamide, having a melting point of 122.8-124.0 C. (corn).

Example 17, 2,5-dichloro-3-nitro-N-(n-pentyDbenzamide, having a melting point of 105.8-106.4 C. (corr.).

Example 18, 2,5-dichloro-3-nitro-N-allylbenzamide, having a melting point of 13'9.0-l40.2 C. (corn).

Example 19, 2,5-dichloro-3-nitro-N-(n-hexyl)benzamide, having a melting point of 99-103 C.

Example 20, 2,5-dichloro-3nitro-N-isopropylbenzamide, having a melting point of 142.0-143.0 C. (corn).

Example 21, l,2-bis(2,S-dichloro-3-nitrobenzoyl)-hydrazine, having a melting point of 331.5-334 C. (corr.).

Example 22, 3-(2,5-dichloro-3-nitrobenzoylamino)benzoic acid.

Example 23, 2,5-dichloro-3-nitro-N-[2-(5-nitro)furyl]- benzamide.

Example 24, 2,5-dichloro-3-nitro-N-(2-pyridyl)benzamide.

Example 25, 2,5-dichloro-3-nitro-N-(2-thienyl)benzamide.

Example 26, 2,5-dichloro-3-nitro-benzanilide.

Example 27, 2,5-dichloro-3-nitro-N-methyllbenzanilide.

Example 28, 2,5-dichloro-3-nitro-N-benzylbenzamide.

Example 29, 2,5-dichloro-3-nitro-N-(2,4-dichlorobenzyl)benzamide.

Example 30, 2,5 dichloro 3 nitro N (3',4',5'-trimethoxybenzanilide.

Example 31, 2,5-di'bromo-3-nitrobenzamide is prepared in the manner described in Example l from ammonium hydroxide, thionyl chloride, and 2,5-dibrorno-3-nitrobenzoic acid. The latter compound is prepared from p-dibromobenzene and phosgene in the presence of aluminium chloride under FriedeLCrafts reaction conditions, followed by hydrolysis to 2,5-dibr0mobenzoic acid and subsequent nitration with mixed nitric and sulfuric acids.

Example 32, 2,5-dichloro-3-nitro-N,N-dimethylbenzhydrazide is prepared from 2,5-dichloro-3-nitrobenzoyl chloride and N ,N-dimethylhydrazine.

Example 33, N-(2,S-dichloro-3-nitrobenzoyl)-N'-isopropyl idenehydrazine is prepared by reacting 2,5-dichloro- 3-nit'robenzoyl chloride with isopropylidenehydrazine (acetone hydrazone).

Example 34, 2,5-dichloro-3-nitrobenzonitrile is prepared by refluxing 2,5-dichloro-3-nitrobenzamide with thionyl chloride until the evolution of hydrogen chloride and sulfur dioxide is complete.

Example 35, 2,5-difiuoro-3-nitrobenzamide is prepared in a manner analogous to that described in Example 31, using',p=difiuorobenzene instead of p-dibromobenzene.

Example 36, 2 ,5-diiodo-3-nitrobenzamide is prepared in a mariner analogous to that described in Example 31, u'singfp diiodobenzene instead of p-dibromo'benzene.

Example 37, 2,5-dichloro-N,N-diphenyl-3-nitrobenzamide is prepared in a manner analogous to that described in Example 1, using diphenylamine instead of methylamine. 1

Example 38, N,N-dibenzyl-2,5-dichloro-3-nitrobenzamide is prepared in a manner analogous to that described in Example 1, using dibenzylamine instead of methylamine.

Example 39, 2,5-dichloro-3-nitro-N--(2-oxazolyl)benzamide is prepared in a manner analogous to that described in Example 1, using Z-aminooxazole instead of methylamine.

Example 40, 2,5-dichloro-3-nitro-N-(3-pyrazolyl)benzamide is prepared in a manner analogous to that described in Example 1, using 3-aminopyrazole instead of methylamine.

We claim:

1. A compound of the formula Hal Hal NO:

wherein X is a member selected from the group consisting of CONHR, C -ONRR, CONHNHCORQ, CONHNRR', and CONHOH, and Hal is halogen, wherein R and R are members selected from the group consisting of loweralkyl, lower-alkenyl, phenyl, benzyl, pyridyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, and furyl.

2. A compound of the formula CIJONHR Hal Hal --NO r wherein R is lower alkyl.

3. 2,S'dichloro3-nitro-Nmethyl benzan1ide. 2,5-dichloro-3-nitro-N-ethylbenzamide. 2,5-dichloro-3-nitro-N'(2-hydroxyethyl)benzamide. 1,2-bis 2,5-dichloro-3 -'nitrobenzoyl hydrazine. 2,5-dichloro-3-nitro-N,N dimethy-l'benzamide, 2,5-dichloro-3,4'-dinitrobenzanilide. 2,5dichloro-3-nitro-N-(2-thiazolyl) benzamide. 10. 2,5 dichloro 3 -nitro N (3 dimethylaminopropyl benzamide.

(References on following page) 7 References Cited UNITED STATES PATENTS 3,228,833 1/1966 Crounse et a1.

FOREIGN PATENTS 830,060 3/1960 Great Britain.

8 OTHER REFERENCES Degering: Organic Nitrogen Compounds, 1950, pp.

393-4. NICHOLAS S. RIZZO, Primary Examiner.

R. GALLAGHER, Assistant Examiner.

US. Cl. XR. 

1. A COMPOUND OF THE FORMULA 